1.
Sigma receptor
–
The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP, SA4503, ditolylguanidine, dimethyltryptamine, and siramesine. However, such drugs had no clinically relevant affinities for μ, κ, however, pharmacological testing indicated that the σ-receptors were activated by drugs completely unrelated to the opioids, and their function was unrelated to the function of the opioid receptors. When the σ1 receptor was isolated and cloned, it was found to have no similarity to the opioid receptors. At this point, they were designated as a class of receptors. The function of these receptors is poorly understood though an endogenous ligand, activation of σ–receptors by an agonist ligand may induce hallucinogenic effects and also may be responsible for the paradoxical convulsions sometimes seen in opiate overdose. Drugs known to be σ–agonists include cocaine, morphine/diacetylmorphine, opipramol, PCP, fluvoxamine, methamphetamine, dextromethorphan, however the exact role of σ–receptors is difficult to establish as many σ–agonists also bind to other targets such as the κ-opioid receptor and the NMDA glutamate receptor. In animal experiments, σ–antagonists such as rimcazole were able to block convulsions from cocaine overdose, σ–antagonists are also under investigation for use as antipsychotic medications. Physiologic effects when the σ–receptor is activated include hypertonia, tachycardia, tachypnea, antitussive effects, some σ–receptor agonists—such as cocaine, a weak σ–agonist—exert convulsant effects in animals. Behavioral reactions to σ–agonists are rather heterogeneous, some individuals find σ–receptor agonists euphoric with significant anti-depressive effects, other individuals, however, experience dysphoria and often report feelings of malaise or anxiety. Recently selective σ–receptor agonists were shown to produce effects in mice. Sigma Receptor at the US National Library of Medicine Medical Subject Headings

2.
5-MeO-DMT
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5-MeO-DMT is a psychedelic of the tryptamine class. It is found in a variety of plant species, and a single psychoactive toad species. Like its close relatives DMT and bufotenin, it has used as an entheogen in South America. 5-MeO-DMT was first synthesized in 1936, and in 1959 it was isolated as one of the ingredients of Anadenanthera peregrina seeds used in preparing Yopo snuff. It is metabolized mainly by CYP2D6, 5-MeO-DMT is a sacrament of the Church of the Tree of Life. From approximately 1971 to the late 1980s, 5-MeO-DMT was discreetly available to its members, between 1970 and 1990 smoking of 5-MeO-DMT on parsley was probably one of the two most common forms of ingestion in the United States. 5-MeO-DMT is a derivative of DMT. Its pharmacological action is mainly through serotonin receptors, specifically, it shows high affinity for the 5-HT2 and 5-HT1A subtypes. Additional mechanisms of such as inhibition of monoamine reuptake may be involved also. As of October 2015, 5-MeO-DMT is a substance in China. As a structural analog of N, N-dimethyltryptamine, 5-MeO-DMT is a Schedule 9 prohibited substance under the Poisons Standard, 5-MeO-DMT has been controlled in Turkey since December 2013. 5-MeO-DMT was made a Schedule I controlled substance in January 2011, 4-MeO-DMT 5-MeO-AMT 5-MeO-DIPT 5-EtO-DMT Dimemebfe List of entheogens TiHKAL #38 on Erowid and Erowids 5-MeO-DMT Vault 5-MeO-DMT Entry in TiHKAL • info PsychonautWikis 5-meo-dmt

3.
Arketamine
–
Arketamine, also -ketamine or --ketamine, is the - enantiomer of ketamine. On the other hand, it appears to be effective as an antidepressant. Relative to esketamine, arketamine possesses 4–5 times lower affinity for the PCP site of the NMDA receptor, in accordance, arketamine is significantly less potent than racemic ketamine and especially esketamine in terms of anesthetic, analgesic, and sedative-hypnotic effects. Esketamine inhibits the dopamine transporter about 8-fold more potently than does arketamine, arketamine and esketamine possess similar potency for interaction with the muscarinic acetylcholine receptors. Paradoxically, arketamine shows greater and longer-lasting rapid antidepressant effects in animal models of relative to esketamine. The picture is unclear however, and other mechanisms have also been implicated, as such, arketamine may have a lower propensity for producing psychotomimetic effects and a lower abuse potential in addition to superior antidepressant efficacy

4.
Captodiame
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Captodiame, also known as captodiamine, is an antihistamine sold under the trade names Covatine, Covatix, and Suvren which is used as a sedative and anxiolytic. It is a derivative of diphenhydramine, a 2004 study suggested captodiame may be helpful in preventing benzodiazepine withdrawal syndrome in people discontinuing benzodiazepine treatment. In addition to its actions as an antihistamine, captodiamine has been found to act as a 5-HT2C receptor antagonist and σ1 receptor and it produces antidepressant-like effects in rats. However, captodiamine is unique among antidepressant-like drugs in that it increases brain-derived neurotrophic factor levels in the hypothalamus and this unique action may be related to its ability to attenuate stress-induced anhedonia and corticotropin-releasing factor signaling in the hypothalamus. Friedel-Crafts acylation of the ether of thiophenol with benzoyl chloride gives the corresponding benzophenone. Reduction of the ketone with zinc/NaOH followed by treatment with HCl in ether affords the benzhydryl chloride, displacement of the halogen with thiourea gives, by reaction of the last at its most nucleophilic center, the isothiouronium salt. Hydrolysis of the leads to the sulfur analog of a benzhydrol. Alkylation of the salt of this last with N-dimethylamine affords captodiame

5.
Cocaine
–
Cocaine, also known as coke, is a strong stimulant mostly used as a recreational drug. It is commonly snorted, inhaled, or injected into the veins, mental effects may include loss of contact with reality, an intense feeling of happiness, or agitation. Physical symptoms may include a fast heart rate, sweating, high doses can result in very high blood pressure or body temperature. Effects begin within seconds to minutes of use and last between five and ninety minutes, Cocaine has a small number of accepted medical uses such as numbing and decreasing bleeding during nasal surgery. Cocaine is addictive due to its effect on the pathway in the brain. After a short period of use, there is a risk that dependence will occur. Its use also increases the risk of stroke, myocardial infarction, lung problems in those who smoke it, blood infections, Cocaine sold on the street is commonly mixed with local anesthetics, cornstarch, quinine, or sugar which can result in additional toxicity. Following repeated doses a person may have decreased ability to feel pleasure, Cocaine acts by inhibiting the reuptake of serotonin, norepinephrine, and dopamine. This results in concentrations of these three neurotransmitters in the brain. It can easily cross the barrier and may lead to the breakdown of the barrier. Cocaine is made from the leaves of the plant which are mostly grown in South America. In 2013,419 kilograms were produced legally and it is estimated that the illegal market for cocaine is 100 to 500 billion USD each year. With further processing crack cocaine can be produced from cocaine, after cannabis, cocaine is the most frequently used illegal drug globally. Between 14 and 21 million people use the drug each year, use is highest in North America followed by Europe and South America. Between one and three percent of people in the world have used cocaine at some point in their life. In 2013 cocaine use resulted in 4,300 deaths. The leaves of the plant have been used by Peruvians since ancient times. Cocaine was first isolated from the leaves in 1860, since 1961 the international Single Convention on Narcotic Drugs has required countries to make recreational use of cocaine a crime

6.
Cyclazocine
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Cyclazocine is a mixed opioid agonist/antagonist related to dezocine, pentazocine and phenazocine. This family of drugs is called the benzomorphans or benzazocines. It is a KOR agonist and MOR partial agonist, and also has affinity for the DOR. Research into the use of cyclazocine for the treatment of patients with depression was undertaken by Fink. It showed that 8 out of 10 patients experienced moderate improvement, and MOR, although the side-effect threshold is often lower than the lowest effective dose

7.
Dehydroepiandrosterone
–
Dehydroepiandrosterone, also known as androstenolone, is an endogenous steroid hormone. However, DHEA also has a variety of biological effects in its own right, binding to an array of nuclear and cell surface receptors. Exogenous dehydroepiandrosterone used as a medication is often called prasterone, in women with adrenal insufficiency and the healthy elderly there is insufficient evidence to support the use of DHEA. DHEA is sometimes used as an androgen in hormone replacement therapy for menopause, a long-lasting ester prodrug of DHEA, prasterone enanthate, is used in combination with estradiol valerate for this indication. DHEA is produced naturally in the body, but the long-term effects of its use are largely unknown. In the short term, several studies have noted few adverse effects, in a study by Chang et al. DHEA was administered at a dose of 200 mg/day for 24 weeks with slight androgenic effects noted, another study utilized a dose up to 400 mg/day for 8 weeks with few adverse events reported. A longer term study followed patients dosed with 50 mg of DHEA for 12 months with the number, another study delivered a dose of 50 mg of DHEA for 10 months with no serious adverse events reported. As a hormone precursor, there has been a smattering of reports of side effects caused by the hormone metabolites of DHEA. It is not known whether DHEA is safe for long-term use, some researchers believe DHEA supplements might actually raise the risk of breast cancer, prostate cancer, heart disease, diabetes, and stroke. DHEA may stimulate tumor growth in types of cancer that are sensitive to hormones, such as types of breast, uterine. DHEA may increase prostate swelling in men with benign prostatic hyperplasia, high doses may cause aggressiveness, irritability, trouble sleeping, and the growth of body or facial hair on women. It also may stop menstruation and lower the levels of HDL, other reported side effects include acne, heart rhythm problems, liver problems, hair loss, and oily skin. It may also alter the bodys regulation of blood sugar, patients on hormone replacement therapy may have more estrogen-related side effects when taking DHEA. This supplement may also interfere with other medicines, and potential interactions between it and drugs and herbs are possible, DHEA is produced from cholesterol through two cytochrome P450 enzymes. Cholesterol is converted to pregnenolone by the enzyme P450 scc, then another enzyme, CYP17A1, converts pregnenolone to 17α-hydroxypregnenolone, regular exercise is known to increase DHEA production in the body. Calorie restriction has also shown to increase DHEA in primates. Some theorize that the increase in endogenous DHEA brought about by calorie restriction is partially responsible for the life expectancy known to be associated with calorie restriction

8.
Prasterone
–
Dehydroepiandrosterone, also known as androstenolone, is an endogenous steroid hormone. However, DHEA also has a variety of biological effects in its own right, binding to an array of nuclear and cell surface receptors. Exogenous dehydroepiandrosterone used as a medication is often called prasterone, in women with adrenal insufficiency and the healthy elderly there is insufficient evidence to support the use of DHEA. DHEA is sometimes used as an androgen in hormone replacement therapy for menopause, a long-lasting ester prodrug of DHEA, prasterone enanthate, is used in combination with estradiol valerate for this indication. DHEA is produced naturally in the body, but the long-term effects of its use are largely unknown. In the short term, several studies have noted few adverse effects, in a study by Chang et al. DHEA was administered at a dose of 200 mg/day for 24 weeks with slight androgenic effects noted, another study utilized a dose up to 400 mg/day for 8 weeks with few adverse events reported. A longer term study followed patients dosed with 50 mg of DHEA for 12 months with the number, another study delivered a dose of 50 mg of DHEA for 10 months with no serious adverse events reported. As a hormone precursor, there have reports of side effects possibly caused by the hormone metabolites of DHEA. It is not known whether DHEA is safe for long-term use, some researchers believe DHEA supplements might actually raise the risk of breast cancer, prostate cancer, heart disease, diabetes, and stroke. DHEA may stimulate tumor growth in types of cancer that are sensitive to hormones, such as types of breast, uterine. DHEA may increase prostate swelling in men with benign prostatic hyperplasia, high doses may cause aggressiveness, irritability, trouble sleeping, and the growth of body or facial hair on women. It also may stop menstruation and lower the levels of HDL, other reported side effects include acne, heart rhythm problems, liver problems, hair loss, and oily skin. It may also alter the bodys regulation of blood sugar, patients on hormone replacement therapy may have more estrogen-related side effects when taking DHEA. This supplement may also interfere with other medicines, and potential interactions between it and drugs and herbs are possible, DHEA is produced from cholesterol through two cytochrome P450 enzymes. Cholesterol is converted to pregnenolone by the enzyme P450 scc, then another enzyme, CYP17A1, converts pregnenolone to 17α-hydroxypregnenolone, regular exercise is known to increase DHEA production in the body. Calorie restriction has also shown to increase DHEA in primates. Some theorize that the increase in endogenous DHEA brought about by calorie restriction is partially responsible for the life expectancy known to be associated with calorie restriction

9.
Dehydroepiandrosterone sulfate
–
Dehydroepiandrosterone sulfate, also known as prasterone sulfate, is a naturally occurring, endogenous androstane steroid and neurosteroid and the 3β-sulfate ester of dehydroepiandrosterone. As the sodium salt, prasterone sodium sulfate, DHEA-S is used as a drug in Japan in the treatment of insufficient cervical ripening. Dehydroepiandrosterone sulfate is produced by the addition of a group, catalyzed by the sulfotransferase enzymes SULT1A1 and SULT1E1. DHEA sulfate can also be back-converted to DHEA through the action of steroid sulfatase, in the zona reticularis layer of the adrenal cortex, DHEA-sulfate is generated by SULT2A1. This layer of the cortex is thought to be the primary source of serum DHEA-sulfate. DHEA sulfate levels decline as a person ages as the reticularis layer diminishes in size, dehydroepiandrosterone sulfate levels above 1890 micromol/L or 700-800 µg/dL are highly suggestive of adrenal dysfunction because DHEA-S is made by the adrenal glands and also synthesized in brain. The presence of DHEA-S is therefore used to rule out ovarian or testicular origin of excess androgen, the Endocrine Society recommends against the therapeutic use of DHEA sulfate in both healthy women and those with adrenal insufficiency, as its role is not clear from studies performed so far

10.
Prasterone sulfate
–
Dehydroepiandrosterone sulfate, also known as prasterone sulfate, is a naturally occurring, endogenous androstane steroid and neurosteroid and the 3β-sulfate ester of dehydroepiandrosterone. As the sodium salt, prasterone sodium sulfate, DHEA-S is used as a drug in Japan in the treatment of insufficient cervical ripening. Dehydroepiandrosterone sulfate is produced by the addition of a group, catalyzed by the sulfotransferase enzymes SULT1A1 and SULT1E1. DHEA sulfate can also be back-converted to DHEA through the action of steroid sulfatase, in the zona reticularis layer of the adrenal cortex, DHEA-sulfate is generated by SULT2A1. This layer of the cortex is thought to be the primary source of serum DHEA-sulfate. DHEA sulfate levels decline as a person ages as the reticularis layer diminishes in size, dehydroepiandrosterone sulfate levels above 1890 micromol/L or 700-800 µg/dL are highly suggestive of adrenal dysfunction because DHEA-S is made by the adrenal glands and also synthesized in brain. The presence of DHEA-S is therefore used to rule out ovarian or testicular origin of excess androgen, the Endocrine Society recommends against the therapeutic use of DHEA sulfate in both healthy women and those with adrenal insufficiency, as its role is not clear from studies performed so far

11.
Dextrallorphan
–
Dextrallorphan is an opioid derivative chemical of the morphinan class that is used in scientific research. It acts as a σ1 receptor agonist and NMDA receptor antagonist and it has no significant affinity for the σ2, μ-opioid, or δ-opioid receptor, or for the serotonin or norepinephrine transporter. As an NMDA receptor antagonist, in vivo, it is twice as potent as dextromethorphan. Dextrallorphan is often used in research to block σ1 receptor sites so that σ2 receptor sites can be studied and it was hypothesized that both of these sigma receptors were opioid receptors, due to their affinity for psychoactive drugs. However, it is now understood that they are non-opioid receptors that bind to certain psychoactive drugs, one example of dextrallorphan being used to mask σ1 receptor sites was seen in a study on the localization of the σ2 receptor in detergent-resistant lipid raft domains. Dextrallorphan was used in Spraque-Dawley rats to study cerebellar Purkinje neurons electrophysical responses to the drug when it was applied iontophoretically as a sigma receptor ligand, dextrallorphan increased the firing rate by 14%, suggesting that sigma ligands alter the spontaneous firing of Purkinje neurons and cause motor effects. In another study, dextrallorphan, along with other derivatives, was found to be a potent inhibitor of etorphine-inaccessible sites in the guinea-pig brain. Dextrallorphan was of the top three most potent opioid inhibitors of those studied, with a concentration of 67 nM required to show 50% inhibition, in 1955, dextrallorphan has been used to study inhibition of cholinesterases and to look at the relationship between analgetics and acetylcholine metabolism. It was found that dextrallorphan inhibits 25% of bovine erythrocyte cholinesterase at a dose of 10−3 mole/liter, however, at this dose the drug showed no effect on the gut tone. Simultaneously, dextrallorphan showed no analgesia and no change in intestinal tone, with these results dextrallorphan helped proved that there is no correlation between the inhibition of cholinesterase systems and analgetic or intestinal effects. In 1979, dextrallorphan was found to have a half maximal inhibitory concentration for binding to the pituitary and brain receptor of 10,000 ±1000 nM and 10,000 ±1500 nM, respectively. While its stereoisomer, levallorphan, had a 10,000 times more potent dose, thus proving that binding to these receptors is stereospecific

12.
Dextrorphan
–
Dextrorphan is a psychoactive drug of the morphinan chemical class which acts as an antitussive or cough suppressant and dissociative hallucinogen. It is the dextrorotatory-stereoisomer of racemorphan, the levo-half being levorphanol, dextrorphan is produced by O-demethylation of dextromethorphan by CYP2D6. Dextrorphan is an NMDA antagonist and contributes to the effects of dextromethorphan. σ1 and σ2 sigma receptor agonist, serotonin reuptake inhibitor μ-, and κ-opioid receptor agonist α3β4, α4β2, and α7 nicotinic acetylcholine receptor antagonist. Glycine receptor antagonist L-Type voltage-gated calcium channel blocker, the pharmacology of dextrorphan is similar to that of dextromethorphan. Dextrorphan was formerly a Schedule I controlled substance in the United States, cough medicine Dextrallorphan Dextromethorphan Dissociative Levallorphan Morphanol Morphinan Nortilidine O-Desmethyltramadol Oxilorphan

13.
N,N-Dimethyltryptamine
–
N, N-Dimethyltryptamine is a powerful psychedelic compound of the tryptamine family. It is a analog of serotonin and melatonin and a functional analog of other psychedelic tryptamines such as 4-AcO-DMT, 5-MeO-DMT, 5-HO-DMT, psilocybin. Historically, it has been consumed by indigenous Amazonian cultures in the form of ayahuasca for divinatory and it was first synthesised in 1931, and in 1946, microbiologist Oswaldo Gonçalves de Lima discovered its natural presence in plants. In the 1960s, it was detected in mammalian organisms as well, DMT is known for its relatively short duration of action, intense effects and rapid onset. For that reason, DMT was known as a trip during the 1960s in the United States. DMT can be inhaled, injected, or orally ingested, and its effects depend on the dose, the effects last a short period of time,5 to 15 min. Longer effects can be achieved by oral ingestion, over 3 hours, DMT can produce psychedelic experiences involving euphoria and hallucinations. In most countries, DMT is illegal, the dependence potential of DMT and the risk of sustained psychological disturbance are minimal when used for religious ceremonies. DMT, like most psychedelics, is considered to be neither addictive, growth hormone blood levels rose equally in response to all doses of DMT, and melatonin levels were unaffected. Several scientific experimental studies have tried to measure subjective experiences of altered states of consciousness induced by drugs, here it is important to notice that in scientific studies measurements are conducted in laboratories under highly controlled and safe conditions. It appears that the set and setting have an influence, therefore if the drug is taken in different settings. In the 1990s, Strassman and his colleagues conducted a five year long DMT study at the University of New Mexico, the results provided insight about the quality of subjective psychedelic experiences. In this study received the DMT dosage intravenously via injection. Lower doses produced somaesthetic and emotional responses, but not hallucinogenic experiences, in contrary, higher doses researchers labeled as hallucinogenic that elicited intensely colored, rapidly moving display of visual images, formed, abstract or both. Comparing to other sensory modalities the most affected was visual domain, Strassman also stressed the importance of the context where drug has been taken. He claimed that DMT has no effects of itself, rather the context when. It appears that DMT can produce a hallucinogenic experience and it can induce a state or feeling to a person that she or he is able to communicate with other intelligent-life forms. High doses of DMT produce a state that involves sense of another intelligence that people sometimes describe as super-intelligent

14.
Eliprodil
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Eliprodil is a NMDA antagonist drug candidate that failed a Phase III clinical trial for the treatment of acute ischemic stroke in 1996, sponsored by Synthélabo Recherche. NMDA receptors are a key component in mediating glutamate-induced excitotoxicity, after a traumatic brain injury, neurons become deprived of glucose and oxygen. These neurons quickly lose ATP and become depolarized, which releases glutamate, the intracellular buildup of glutamate triggers the overstimulation of AMPA and NMDA receptors. This, in turn, causes an influx of Na+ and Ca2+, therefore, when NMDA receptors are activated, there is an increase in intracellular Ca2+ concentration. High Ca2+ causes fatal metabolic consequences, including cell death

15.
Fabomotizole
–
Fabomotizole is an anxiolytic drug launched in Russia in the early 2000s. It produces anxiolytic and neuroprotective effects without any sedative or muscle relaxant actions, fabomotizole was shown to inhibit MAO-A reversibly and there might be also some involvement with serotonin receptors. Clinical trials have shown fabomotizole to be tolerated and reasonably effective for the treatment of anxiety. Experiments of mice have shown antimutagenic and antiteratogenic properties, fabomotizole has found little clinical use outside Russia and has not been evaluated by the FDA

17.
Ketamine
–
Ketamine, sold under the brand name Ketalar among others, is a medication mainly used for starting and maintaining anesthesia. It induces a state while providing pain relief, sedation. Other uses include for chronic pain and for sedation in intensive care, heart function, breathing, and airway reflexes generally remain functional. Effects typically begin within five minutes when given by injection with the main effects lasting up to 25 minutes, common side effects include psychological reactions as the medication wears off. These reactions may include agitation, confusion, or hallucinations, elevated blood pressure and muscle tremors are relatively common, while low blood pressure and a decrease in breathing are less so. Spasms of the larynx may rarely occur, Ketamine has been classified as an NMDA receptor antagonist, it also acts on opioid receptors and monoamine transporters among others. It is on the World Health Organizations List of Essential Medicines and it is available as a generic medication. The wholesale cost in the world is between 0.08 and 0.32 USD per dose. Ketamine is also used as a recreational drug, Ketamine is frequently used in severely injured people and appears to be safe in this group. A2011 clinical practice guideline supports the use of ketamine as a sedative in emergency medicine. It is the drug of choice for people in traumatic shock who are at risk of hypotension, low blood pressure is harmful in people with severe head injury and ketamine is least likely to cause low blood pressure, often even able to prevent it. The effect of ketamine on the respiratory and circulatory systems is different from that of other anesthetics, when used at anesthetic doses, it will usually stimulate rather than depress the circulatory system. It is sometimes possible to perform ketamine anesthesia without protective measures to the airways, Ketamine is considered relatively safe because protective airway reflexes are preserved. Ketamine is used as a bronchodilator in the treatment of severe asthma, however, evidence of clinical benefit is limited. Ketamine may be used for pain management. Low doses of ketamine reduce morphine use and nausea and vomiting after surgery, high quality evidence in acute pain is insufficient to determine if ketamine is useful in this situation. It may also be used as an analgesic with opiates to manage otherwise intractable pain. It has the benefit of counteracting spinal sensitization or wind-up phenomena experienced with chronic pain

18.
MDMA
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3, 4-Methylenedioxymethamphetamine, commonly known as ecstasy, is a psychoactive drug used primarily as a recreational drug. Desired effects include increased empathy, euphoria, and heightened sensations, when taken by mouth, effects begin after 30–45 minutes and last 3–6 hours. It is also sometimes snorted or smoked, as of 2017, MDMA has no accepted medical uses. Adverse effects of MDMA use include addiction, memory problems, paranoia, difficulty sleeping, teeth grinding, blurred vision, sweating, use may also lead to depression and fatigue. Deaths have been reported due to increased temperature and dehydration. MDMA increases the release and slows the reuptake of the serotonin, dopamine. It has stimulant and psychedelic effects, the initial increase is followed by a short-term decrease in the neurotransmitters. MDMA belongs to the substituted methylenedioxyphenethylamine and substituted amphetamine classes of drugs, MDMA was first made in 1912. It was used to improve psychotherapy beginning in the 1970s and became popular as a drug in the 1980s. MDMA is commonly associated with parties, raves, and electronic dance music. It is often mixed with other substances such as ephedrine, amphetamine. In 2014, between 9 and 29 million people between the ages of 15 and 64 used ecstasy and this was broadly similar to the percentage of people who use cocaine, amphetamines, and opioids, but fewer than for cannabis. In the United States, about 0.9 million people used ecstasy in 2010, MDMA is generally illegal in most countries. Limited exceptions are made for research. Researchers are investigating whether a few low doses of MDMA may assist in treating severe, in November 2016, phase 3 clinical trials for PTSD were approved by the United States Food and Drug Administration to assess effectiveness and safety. As of 2017, MDMA has no accepted medical indications, before it was widely banned, it saw limited use in therapy. A small number of therapists continue to use MDMA in therapy despite its illegal status, MDMA is often considered the drug of choice within the rave culture and is also used at clubs, festivals and house parties. In the rave environment, the effects from the music

19.
Methamphetamine
–
Methamphetamine is a strong central nervous system stimulant that is mainly used as a recreational drug and less commonly as a treatment for attention deficit hyperactivity disorder and obesity. Methamphetamine was discovered in 1893 and exists as two enantiomers, levo-methamphetamine and dextro-methamphetamine, Methamphetamine properly refers to a specific chemical, the racemic free base, which is an equal mixture of levomethamphetamine and dextromethamphetamine in their pure amine forms. Dextromethamphetamine is a much stronger CNS stimulant than levomethamphetamine, both methamphetamine and dextromethamphetamine are illicitly trafficked and sold owing to their potential for recreational use. Levomethamphetamine is available as a drug for use as an inhaled nasal decongestant in the United States. While dextromethamphetamine is a potent drug, racemic methamphetamine is sometimes illicitly produced due to the relative ease of synthesis. In low doses, methamphetamine can elevate mood, increase alertness, concentration and energy in fatigued individuals, at higher doses, it can induce psychosis, breakdown of skeletal muscle, seizures and bleeding in the brain. Chronic high-dose use can precipitate unpredictable and rapid mood swings, prominent delusions, Methamphetamine is known to have a high addiction liability and dependence liability. Heavy recreational use of methamphetamine may lead to a post-acute-withdrawal syndrome, unlike amphetamine, methamphetamine is neurotoxic to human midbrain dopaminergic neurons. It has also shown to damage serotonin neurons in the CNS. This damage includes adverse changes in structure and function, such as reductions in grey matter volume in several brain regions. Methamphetamine belongs to the phenethylamine and substituted amphetamine chemical classes. It is related to the other dimethylphenethylamines as an isomer of these compounds. Methamphetamine is sometimes prescribed off label for narcolepsy and idiopathic hypersomnia, in the United States, methamphetamines levorotary form is available in some over-the-counter nasal decongestant products. As methamphetamine is associated with a potential for misuse, the drug is regulated under the Controlled Substances Act and is listed under schedule II in the United States. Methamphetamine hydrochloride dispensed in the United States is required to include a warning regarding its potential for recreational misuse. Methamphetamine is often used recreationally for its effects as a potent euphoriant and stimulant as well as aphrodisiac qualities, according to a National Geographic TV documentary on methamphetamine, an entire subculture known as party and play is based around methamphetamine use. Members of this San Francisco sub-culture, which consists almost entirely of gay male methamphetamine users, due to its strong stimulant and aphrodisiac effects and inhibitory effect on ejaculation, with repeated use, these sexual encounters will sometimes occur continuously for several days on end. The crash following the use of methamphetamine in this manner is often severe

20.
Methoxetamine
–
Methoxetamine, or 3-MeO-2-Oxo-PCE is a dissociative drug that has been sold as a designer drug. Methoxetamine differs from many such as ketamine and phencyclidine that were developed as pharmaceuticals in that it was designed for grey market distribution. Methoxetamine hydrochloride is soluble in ethanol up to 10 mg/ml at 25 °C, by July 2011, the EMCDDA had identified 58 websites selling the compound at a cost of 145–195 euros for 10 grams. MXE remains popular despite bans in many countries, Methoxetamine is reported to have a similar effect to ketamine, with increased potency and duration. Recreational use of Methoxetamine has been associated with hospitalizations from high and/or combined consumption in the US, acute reversible cerebellar toxicity has been documented in three cases of hospital admission due to methoxetamine overdose, lasting for between one and four days after exposure. Like ketamine, methoxetamine has been found to produce bladder inflammation and fibrosis after high dose, reports of urotoxicity in humans have yet to appear in the medical literature. It has been hypothesized that MXE may be an effective, fast-acting antidepressant like other NMDA antagonists with possibly even superior efficacy compared to ketamine and its activity at other receptors may contribute to this. Methoxetamine is one of a few substances which has been controlled under the UN1971 Convention on Psychotropic Substances since its inception and it was made a schedule 2 drug in November 2016. It is an example of a drug being put into schedule II without having an existing medical use. MXE became classified as a narcotic in Brazil in February 2014, as of October 2015 MXE is a controlled substance in China. On 16 June 2014, the European Commission proposed that MXE be banned across the European Union and this is following the procedure for risk-assessment and control of new psychoactive substances set up by the Council, Decision 2005/387/JHA. Methoxetamine is a controlled substance making it illegal to produce, sell or possess in The Republic of Poland as of 1 July 2015, MXE became classified as a narcotic in Sweden in late February 2012. MXE became a substance in Japan from 1 July 2012. MXE has been a substance in Russia since October 2011. MXE has been illegal in Switzerland since December 2011, MXE became classified as an illegal narcotic in Israel on May 2012. Prior to March 2012, MXE was not controlled by the UKs Misuse of Drugs Act, in April 2012, methoxetamine was placed under temporary class drug control, which prohibits its import and sale for 12 months. The report went on to suggest that all analogues of MXE should also become class B drugs, MXE ceased to be covered by the temporary prohibition on 26 February 2013, when it became classified as a Class B drug. In September 2015, a bill was introduced into Congress that sought to make MXE a Schedule I substance, Methoxetamine is a Schedule I controlled substance in the state of Alabama making it illegal to buy, sell, or possess in Alabama

21.
Nepinalone
–
Its brand names include Placatus, Tussolvina, and Nepitus. The effect is evident after 20–30 minutes after administration and persists for at least 4 hours and it acts primarily at the level of the CNS, but also shows a slight activity in inhibiting the bronchospasm. In such use, it is less effective than codeine and more effective than dextromethorphan in inhibiting the tussivo stimulus

22.
Noscapine
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Noscapine is a benzylisoquinoline alkaloid from plants of the poppy family, without painkilling properties. This agent is used for its antitussive effects. Noscapine is often used as an antitussive medication, a 2012 Dutch guideline, however, does not recommend its use for coughing. Noscapine also has properties, inhibiting microtubule interactions, thereby stopping cell proliferation. The drug should not be taken with any MAOIs, as unknown, noscapine should not be taken in conjunction with warfarin as the anticoagulant effects of warfarin may be increased. Noscapines antitussive effects appear to be mediated by its σ–receptor agonist activity. Evidence for this mechanism is suggested by evidence in rats. Pretreatment with rimcazole, a σ-specific antagonist, causes a dose-dependent reduction in activity of noscapine. Noscapine, and its synthetic derivatives called noscapinoids, are known to interact with microtubules and inhibit cell proliferation The lactone ring is unstable. The opposite reaction is presented in acidic media, the bond connecting the two optically active carbon atoms is also unstable. In aqueous solution of acid and heating it dissociates into cotarnine. When noscapine is reduced with zinc/HCl, the bond C1−C3′ saturates, noscapine was first isolated and characterized in chemical breakdown and properties in 1817 under the denomination of Narcotine by Pierre Robiquet, a French chemist in Paris. Many of the enzymes in the biosynthetic pathway was elucidated by the discovery of a 10 gene operon-like cluster named HN1. In 2016, the pathway of noscapine was reconstituted in yeast cells. Although produced at low yields, it is hoped this technology could be used in the future as a way of decreasing a drugs production cost, there are anecdotal reports of the recreational use of over-the-counter drugs in several countries, being readily available from local pharmacies without a prescription. The effects, beginning around 45 to 120 minutes after consumption, are similar to dextromethorphan, unlike dextromethorphan, noscapine is not an NMDA receptor antagonist. Noscapine can survive the manufacturing processes of heroin and can be found in street heroin and this is useful for law enforcement agencies, as the amounts of contaminants can identify the source of seized drugs. In 2005 in Liège, Belgium, the average concentration was around 8%

23.
Opipramol
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Opipramol is an antidepressant and anxiolytic used in Germany and other European countries. Although it is a member of the antidepressants, opipramols primary mechanism of action is much different in comparison. Most TCAs act as inhibitors, but opipramol does not. It is a derivative, belonging to dibenzazepine group. Opipramol was developed by Schindler and Blattner in 1961, Opipramol is typically used in the treatment of generalized anxiety disorder and somatoform disorders. Its anxiolysis becomes prominent after only one to two weeks of chronic administration, upon first commencing treatment, opipramol is rather sedating in nature due to its antihistamine properties, but this effect becomes less prominent with time. Opipramols sigma-1 agonistic effects likely impart potent antitussive effects, many other sigma-1 agonists are used for this purpose, experimental animal studies did not indicate injurious effects of opipramol on the embryonic development or the fertility. Opipramol should be prescribed during pregnancy, particularly in the first trimester, Opipramol should not be used during lactation period, since the active ingredient passes into the milk in small quantities. Opipramol acts as a high affinity sigma receptor agonist, primarily at the σ1 subtype and it is this property which is responsible for its therapeutic benefits against anxiety and depression. Opipramol also acts as a low to moderate affinity antagonist for the D2, 5-HT2, H1, H2, H1 and H2 receptor antagonism account for its antihistamine effects, and muscarinic acetylcholine receptor antagonism is responsible for its anticholinergic properties. Sigma receptors are a set of proteins located in the endoplasmic reticulum, σ1 receptors play key role in potentiating intracellular calcium mobilization thereby acting as sensor or modulator of calcium signalling. Occupancy of σ1 receptors by agonists causes translocation of the receptor from endoplasmic reticulum to peripheral areas where the σ1 receptors cause neurotransmitter release, the biphasic action initially makes prompt improvement of tension, anxiety and insomnia. Opipramol is a tranquilizer with a thymoleptic component, after sub-chronic treatment with opipramol σ2 receptors are significantly down-regulated- but not σ1 receptors. Opipramol is rapidly and completely absorbed by the gastrointestinal tract and its terminal plasma half life is 6–11 hours. After single oral administration of 50 mg, the plasma concentration of the drug is reached after 3.3 hours. After single oral administration of 100 mg the maximum concentration is reached after 3 hours. The bioavailability of opipramol amounts to 94%, the plasma protein binding amounts to approximately 91% and the volume of distribution is approximately 10 L/kg. Opipramol is partially metabolized in liver as deshydroxy ethyl-opipramol, 70% is eliminated renally and 10% unaltered

24.
Pentazocine
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Pentazocine is a synthetically-prepared prototypical mixed agonist–antagonist narcotic drug of the benzomorphan class of opioids used to treat moderate to moderately severe pain. Pentazocine is sold under brand names, such as Fortral, Sosegon, Talwin NX, Talwin, Talwin PX, Fortwin. This compound may exist as one of two enantiomers, named -pentazocine and -pentazocine, -pentazocine is a κ-opioid receptor agonist, while -pentazocine is not, instead displaying a ten-fold greater affinity for the σ receptor. Usually, in its oral formulations, it is combined with naloxone so as to prevent people from crushing the tablets, dissolving them in a solvent, related drugs include phenazocine, dezocine, cyclazocine and several chemicals used in research on the central nervous system. Pentazocine is used primarily to treat pain, although its effects are subject to a ceiling effect. It has been discontinued by its sponsor in Australia, although it may be available through the special access scheme. In the 1970s, recreational drug users discovered that combining pentazocine with tripelennamine produced a euphoric sensation, since tripelennamine tablets are typically blue in color and brand-name Pentazocine is known as Talwin, the pentazocine/tripelennamine combination acquired the slang name Ts and blues. It was postulated that the efficacy observed was due to κ-opioid receptor activation-mediated amelioration of hyperdopaminergia in the reward pathways, minimal sedation and no side effects including psychotomimetic effects or worsening of psychosis were observed at the dose administered. Side effects are similar to those of morphine, but pentazocine, high dose may cause high blood pressure or high heart rate. It may also increase cardiac work after myocardial infarction when given intravenously, respiratory depression is a common side effect, but is subject to a ceiling effect, such that at a certain dose the degree of respiratory depression will no longer increase with dose increases. Likewise rarely it has associated with agranulocytosis, erythema multiforme. Severe injection site necrosis and sepsis has occurred with multiple injection of pentazocine lactate, in addition, animal studies have demonstrated that Pentazocine is tolerated less well subcutaneously than intramuscularly. Pentazocine was developed by the Sterling Drug Company, Sterling-Winthrop Research Institute, of Rensselaer and it was approved by the Food and Drug Administration in June 1967 after being favorably reviewed following testing on 12,000 patients in the United States. The analgesic compound was first made at Sterling in 1958, U. S. testing was conducted between 1961 and 1967. By mid 1967 Pentazocine was already being sold in Mexico, England, Pentazocine was originally classified in Schedule V under the Controlled Substances Act but a petition was filed with the D. E. A. on October 1,1971, to shift it to Schedule III. The petition was filed by Joseph L. Fink III, a pharmacist and that petition was accepted for review on November 10,1971 D. E. A. Pentazocine is still classified in Schedule IV under the Controlled Substances Act in the United States, although some states classify it in Schedule III. Internationally, pentazocine is a Schedule III drug under the Convention on Psychotropic Substances, Pentazocine has a DEA ACSCN of 9720, being a Schedule IV substance, the DEA does not assign an annual manufacturing quota for pentazocine for the United States